Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment

Marco C Miotto; Gunnar Weninger; Haikel Dridi; Qi Yuan; Yang Liu; Anetta Wronska; Zephan Melville; Leah Sittenfeld; Steven Reiken; Andrew R Marks

doi:10.1126/sciadv.abo1272

Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment

Sci Adv. 2022 Jul 22;8(29):eabo1272. doi: 10.1126/sciadv.abo1272. Epub 2022 Jul 20.

Authors

Marco C Miotto^{1

2}, Gunnar Weninger^{1

2}, Haikel Dridi^{1

2}, Qi Yuan^{1

2}, Yang Liu^{1

2}, Anetta Wronska^{1

2}, Zephan Melville^{1

2}, Leah Sittenfeld^{1

2}, Steven Reiken^{1

2}, Andrew R Marks^{1

2}

Affiliations

¹ Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
² Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY, USA.

Abstract

Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca²⁺ leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca²⁺ leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

Abstract

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